(a) Field of the Invention
The invention relates to novel substituted 2-azabicyclo-[2.2.2]octane derivatives, to compositions containing the same, and to the method of use thereof in the treatment of central nervous system disorders.
(b) A number of know antipsychotic drugs are disclosed in the art which have been shown to share a selective, high affinity for sigma receptors, which are sites where psychotomimetic opiates, such as (+)-pentazocine and N-allylnormetazocine, act. It has been suggested that the antipsychotic behavioral profile of these antipsychotic drugs can be attributed to their role as competitive antagonists of sigma receptor binding and that a systematic screen for drugs that block sigma receptors may provide a valuable strategy for identifying novel antipsychotic agents. Additionally, it has been shown that the relative potencies of these agents studied in vivo correspond well with their relative binding affinities obtained in vitro. See, for example, Synder and Largent, J. Neuropsychiatry 1989, 1(1), 7-15; Largent, et al., Eur. J. Pharmacol. 1988, 155, 345-347; Deutsch, et al., Clinical Neuropharmacology 1988, 11(2), 105-119; Tayler, et al., Drug Development Research 1987, 11, 65-70; Ferris, et al., Life Sciences 1986, 38(25), 2329-2337; and Su, et al., Neuroscience Letters 1986. 71, 224-228.
(b) Information Disclosure Statement
Moffett, U.S. Pat. No. 3,422,092, issued Jan. 14, 1969, discloses novel 2-carbamoyl and 2-lower-alkylcarbamoyl-2-azabicyclo[2.2.2]octanes which are said to be useful as central nervous system stimulants and lower-alkyl 2-azabicyclo[2.2.2]octane-3-carboxylates which are said to be useful as sedatives and diuretic agents.
Moffett, U.S. Pat. No. 3,497,518, issued Feb. 24, 1970, discloses novel N-(1-alkyl-4-piperidinyl)-2-azabicyclo[2.2.2]-octanes which are said to be useful as central nervous system stimulants.
Fonken, et al., U.S. Pat. No. 3,741,973, issued Jun. 26, 1973, disclose 2-benzoyl-2-azabicyclo[2.2.2]octane as an intermediate and 2-benzoyl-2-azabicyclo[2.2.2]octan-5-one and -5-ol, and 2-benzoyl-2-azabicyclo[2.2.2]octan-6-one and -6-ol as final products. The final products are said to be useful as central nervous system stimulants. A substantially similar disclosure can be found in Fonken, et al., U.S. Pat. No. 3,780,022, issued Dec. 18, 1973.
Michne, U.S. Pat. No. 4,180,667, issued Dec. 25, 1979, discloses, as intermediates, 2-R.sub.1 -3-(4-R.sub.2 -3-R.sub.2 "-5-R.sub.2 '-6-R.sub.2 "'-benzyl)-4-R.sub.3 -5-R.sub.4 -7-Y'-2-azabicyclo[2.2.2]oct-5-enes wherein
R.sub.1 is hydrogen, lower-alkyl, lower-alkanoyl (only when R.sub.4 is hydrogen), lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms;
R.sub.2, R.sub.2 ', R.sub.2 " and R.sub.2 "' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including bromine, chlorine or fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methylenedioxy;
R.sub.3 is hydrogen or lower-alkyl;
R.sub.4 is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkylsulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R.sub.3 and R.sub.4 together are divalent lower-alkylene, --(CH.sub.2).sub.n --, where n is one of the integers 3 or 4; and
Y' is carboxy, cyano, carbo-lower-alkoxy, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl or lower-alkanoyl.
Ezer, et al., U.S. Pat. No. 4,563,464, issued Jan. 7, 1986, disclose 2-azabicyclo[2.2.2]octane derivatives of the formula: ##STR1## wherein:
A is hydrogen, alkoxycarbonyl having from one to four carbon atoms in the alkoxy group, phenylalkoxycarbonyl having from one to four carbon atoms in the alkoxy moiety, alkyl having from one to six carbon atoms, aralkyl containing from one to four carbon atoms in the alkyl moiety or substituted acyl;
R.sub.1 is hydrogen or alkyl having from one to four carbon atoms;
Z is hydrogen or halogen;
X is hydrogen or halogen;
Y is hydrogen or;
X and Y together represent a C--C bond;
W is alkoxycarbonyl having from one to four carbon atoms in the alkoxy moiety, cyano, carboxamido or haloformyl; or if X stands for halogen, W and Y together represent a --CO.sub.2 -- group.
The compounds are said to possess immunosuppressive, anticonvulsive, vasodilating and gastric acid secretion inhibiting properties.
Hartman, et al., U.S. Pat. No. 4,808,718, issued Feb. 28, 1989, disclose a series of substituted 2-azabicyclo[2.2.2]oct-2-ene dicarboxylates which are said to be useful as calcium entry blockers.
Michne, J. Org. Chem. 1976, 41(5), 894-896, discloses, as an intermediate, 3-benzyl-8-ethyl-2-methyl-2-azabicyclo[2.2.2]-oct-7-ene-6-carboxylate.
Buchi, et al., J. Am. Chem. Soc. 1966, 88(13), 3099-3109 disclose methyl 2-benzyl-7-cyano-2-azabicyclo[2.2.2]octane-6-carboxylate hydrochloride without an indication of utility.